Diastereoselective synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors

Abstract

Disclosed is a method of preparing a composition comprising a compound represented Structural Formula (I): The method comprises the step of reacting an aldehyde compound R 10 CHO with an isonitrile compound represented by Structural Formula (II):

What is claimed is:  
     
       1. A method of preparing a composition comprising a compound represented Structural Formula (I):                    
       wherein: 
       R 10  is a substituted aromatic group, provided that when R 20  and R 30  are both —H, then R 10  is not 4-nitrophenyl; and  
       R 20  and R 30  are independently —H, a substituted or unsubstituted aliphatic group or, taken together with the nitrogen atom to which they are bonded, are a substituted or unsubstituted non-aromatic heterocyclic ring;  
       said method comprising the step of reacting an aldehyde compound R 10 CHO with an isonitrile compound represented by Structural Formula (II):                    
       said method being carried out in the absence of a chiral inducing agent. 
     
     
       2. The method of  claim 1  wherein R 20  and R 30  are independently an unsubstituted C1-C5 alkyl group or, taken together with the nitrogen atom to which they are bonded, are an unsubstituted C3-C10 non-aromatic heterocyclic ring and R 10  is a substituted phenyl group. 
     
     
       3. The method of  claim 2  wherein R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are pyrrolidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, piperidinyl or N-phenylpiperazinyl. 
     
     
       4. The method of  claim 1 , wherein the composition is a racemic mixture comprising the compound represented by Structural Formula (I) and its enantiomer, and wherein the method further comprises the steps of: 
       a) resolving the compound represented by Structural Formula (I) from its enantiomer; and  
       b) hydrolyzing the oxazoline group of the resolved compound to form a compound represented by Structural Formula (III):                    
     
     
       5. A method of the of  claim 2  wherein R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are a pyrrolidinyl group. 
     
     
       6. The method of  claim 5  wherein R 10  is phenyl group substituted with —OCH 2 O—, —OCH 2 CH 2 O—, halo, —O(lower alkyl), lower alkyl thiol, —OH, —O(phenyl), —O—CH 2 (phenyl), lower alkyl, amino, lower alkyl amino or lower dialkyl amino. 
     
     
       7. A method of preparing a composition comprising a compound represented by Structural Formula (III):                    
       wherein: 
       R 10  is a substituted or unsubstituted aromatic group, provided that when R 20  and R 30  are both —H, then R 10  is not 3-pyridyl, phenyl or 4-nitrophenyl; and  
       R 20  and R 30  are independently —H, a substituted or unsubstituted aliphatic group or, taken together with the nitrogen atom to which they are bonded, are a substituted or unsubstituted non-aromatic heterocyclic ring;  
       comprising the step of reacting an aldehyde compound R 10 CHO with an isonitrile compound represented by Structural Formula (II):                    
       thereby forming an intermediate represented by Structural Formula (I):                    
       hydrolyzing the oxazoline group in the compound represented by Structural Formula (I), thereby forming the compound represented by Structural Formula (III). 
     
     
       8. The method of  claim 7 , further comprising the step of isolating the compound represented by structural Formula (I) before hydrolyzing the oxazoline group. 
     
     
       9. The method of  claim 7  wherein the second composition is a racemic mixture comprising the compound represented by Structural Formula (III) and it enantiomer, and wherein the method further comprises the steps of: 
       a) resolving the compound represented by Structural Formula (III) from its enantiomer; and  
       b) reacting the resolved compound with an amide reducing agent to form a compound represented by Structural Formula (IV):                    
     
     
       10. The method of  claim 7  wherein R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are pyrrolidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, piperidinyl or N-phenylpiperazinyl. 
     
     
       11. The method of the of  claim 10  wherein: 
       a) R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are a pyrrolidinyl group; and  
       b) R 10  is a phenyl group substituted with —OCH 2 O—, —OCH 2 CH 2 O—, halo, —O(lower alkyl), lower alkyl thiol, —OH, —O(phenyl), —OCH 2 —(phenyl), lower alkyl, amino, lower alkyl amino and lower dialkyl amino.  
     
     
       12. The method of  claim 7  further comprising the step of reacting the compound represented by Structural Formula (III) with an amide reducing agent, thereby forming a third composition comprising a compound represented by Structural Formula (IV):                    
     
     
       13. The method of  claim 12  wherein the third composition is a racemic mixture comprising the compound represented by Structural Formula (IV) and its enantiomer, and wherein the method further comprises the steps of: 
       a) resolving the compound represented by Structural Formula (IV) from its enantiomer; and  
       b) acylating the primary amine group of the resolved compound, thereby forming a fourth composition comprising a compound represented by Structural Formula (V):                    
       wherein R 7  is an aliphatic group. 
     
     
       14. The method of  claim 13  wherein the fourth composition is a racemic mixture of the compound represented by Structural Formula (V) and its enantiomer and wherein the method further comprises the step of resolving the compound represented by Structural Formula (V) from its enantiomer. 
     
     
       15. The method of  claim 12  wherein the amide reducing agent is lithium aluminum hydride. 
     
     
       16. The method of  claim 15  wherein R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are pyrrolidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, piperidinyl or N-phenylpiperazinyl. 
     
     
       17. The method of the of  claim 16  wherein: 
       a) R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are a pyrrolidinyl group; and  
       b) R 10  is a phenyl group substituted with —OCH 2 O—, —OCH 2 CH 2 O—, halo, —O(lower alkyl), lower alkyl thiol, —OH, —O(phenyl), —OCH 2 -(phenyl), lower alkyl, amino, lower alkyl amino and lower dialkyl amino.  
     
     
       18. The method of  claim 12 , further comprising the step of acylating the compound represented by Structural Formula (IV), thereby forming a fourth composition comprising a compound represented by Structural Formula (V):                    
       wherein R 7  is an aliphatic group. 
     
     
       19. The method of  claim 18  wherein the compound represented by Structural Formula (IV) is acylated with R 7 COX, wherein is X is —Cl or an —O—N-succinimidyl group and R 7  is a C 1 -C 30  straight chained alkyl or alkenyl group. 
     
     
       20. The method of  claim 19  wherein R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are pyrrolidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, piperidinyl or N-phenylpiperazinyl. 
     
     
       21. The method of the of  claim 20  wherein: 
       a) R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are a pyrrolidinyl group;  
       b) R 10  is a phenyl group substituted with —OCH 2 O—, —OCH 2 CH 2 O—, halo, —O(lower alkyl), lower alkyl thiol, —OH, —O(phenyl), —O—CH 2 -(phenyl), lower alkyl, amino, lower alkyl amino and lower dialkyl amino; and  
       c) and R 7  is a C 10 -C 16  alkyl group.  
     
     
       22. A method of preparing a product composition comprising a compound represented by Structural Formula (IV):                    
       wherein:  
       R 10  is a substituted or unsubstituted aromatic group; and  
       R 20  and R 30  are independently —H, a substituted or unsubstituted aliphatic group or, taken together with the nitrogen atom to which they are bonded, are a substituted or unsubstituted non-aromatic heterocyclic ring;  
       said method comprising the step of reacting a starting composition with an amide reducing agent, thereby forming the product composition, wherein the starting composition comprises a compound represented by Structural Formula (III):                    
     
     
       23. The method of  claim 22  wherein the amide reducing agent is lithium aluminum hydride. 
     
     
       24. The method of  claim 22  wherein R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are pyrrolidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, piperidinyl or N-phenylpiperazinyl. 
     
     
       25. The method of the of  claim 22  wherein: 
       a) R 20  and R 30 , taken together with the nitrogen atom to which they are bonded, are a pyrrolidinyl group; and  
       b) R 10  is a phenyl group substituted with —OCH 2 O—, —OCH 2 CH 2 O—, halo, —O(lower alkyl), lower alkyl thiol, —OH, —O(phenyl), —OCH 2 -(phenyl), lower alkyl, amino, lower alkyl amino and lower dialkyl amino.  
     
     
       26. The method of  claim 22  wherein the composition is a racemic mixture comprising the compound represented by Structural Formula (IV) and its enantiomer and wherein the method further comprises the step of resolving the compound represented by Structural Formula (IV) from its enantiomer. 
     
     
       27. A method of preparing a composition comprising a first compound represented by the following structural formula:                    
       wherein R 7  is a C 8 -C 18  alkyl group;  
       said method comprising the steps of:  
       a) reacting an aldehyde compound represented by the following structural formula:                    
       with an isonitrile compound represented by the following structural formula:                    
       thereby forming a composition comprising a heterocyclic compound represented by the following structural formula:                    
       b) hydrolyzing the oxazoline group in the heterocyclic compound formed in step a), thereby forming a composition comprising an amide compound represented by the following structural formula:                    
       c) reacting the amide compound formed in step b) with lithium aluminum hydride, thereby forming a composition comprising a cyclic amine compound represented by the following structural formula:                    
       d) and acylating the primary amine group in the cyclic amine compound formed in step c) with R 7 COX, wherein is X is —Cl or an —O—N-succinimidyl group and R 7  is a C 8 -C 18  straight chained alkyl group, thereby forming the composition comprising the first compound. 
     
     
       28. The method of  claim 27 , wherein the composition formed in step a) is a racemic mixture comprising the heterocyclic compound and its enantiomer and wherein the heterocyclic compound is separated from its enantiomer before reacting the heterocyclic compound in step b). 
     
     
       29. The method of  claim 27 , wherein the composition formed in step b) is a racemic mixture comprising the amide compound and its enantiomer and wherein the amide compound is separated from its enantiomer before reacting the amide compound in step c). 
     
     
       30. The method of  claim 27 , wherein the composition formed in step c) is a racemic mixture comprising the cyclic amine compound and its enantiomer and wherein the cyclic amine compound is separated from its enantiomer before reacting the cyclic amine compound in step d). 
     
     
       31. The method of  claim 27 , wherein the composition formed in step d) is a racemic mixture comprising the ceramide-like compound and its enantiomer and wherein the first compound is separated from its enantiomer. 
     
     
       32. The method of  claim 27  wherein R 7  is a C15 alkyl group. 
     
     
       33. A method of preparing a composition comprising a compound represented by Structural Formula (I):                    
       wherein: 
       R 10  is a substituted or unsubstituted 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2-oxazolyl, 4-oxazolyl or 5-oxazolyl, or R 10  is a substituted phenyl, provided that when R 20  and R 30  are both —H, then R 10  is not 3-pyridyl or 4-nitrophenyl; and  
       R 20  and R 30  are independently —H, a substituted or unsubstituted aliphatic group or, taken together with the nitrogen atom to which they are bonded, are a substituted or unsubstituted non-aromatic heterocyclic ring;  
       said method comprising the step of reacting an aldehyde compound R 10 CHO with an isonitrile compound represented by Structural Formula (II):                    
       said method being carried out in the absence of a chiral inducing agent.